Early familial non-medullary thyroid cancer: differences with late-onset and sporadic forms

Objective: This study aimed to compare clinicopathological features of familial non-medullary thyroid cancer (FNMTC) and sporadic non-medullary thyroid cancer (sNMTC) and assess whether age at onset contributes to the different behavior of these 2 entities. Design: A retrospective study including 31 patients with FNMTC, and 31 age- and sex-matched patients with sNMTC. Methods: Histological variant, multifocality, tumor infiltration, angioinvasion, TNM stage, lymph node metastasis, BRAF and p53 expression, ATA risk stratification, and the presence of chronic lymphocytic thyroiditis (CLT) were compared between groups. Then, we identified a cutoff age to stratify patients by age of onset (≤35 vs >35 years). Results: FNMTC presented at a more advanced stage at diagnosis compared to sNMTC, with a higher proportion of medium-high TNM stages. Among FNMTC, early-onset (≤35 years) cases showed higher BRAF expression, more frequent lymph node metastases, a higher proportion of medium-high TNM stages, and intermediate-to-high ATA risk compared to late-onset cases (>35 years). Medium-high TNM stage, BRAF expression, and lymph node metastases were observed more frequently in early onset FNMTC than in age-matched sNMTC. Late-onset FNMTC patients exhibited a higher prevalence of CLT than early-onset FNMTC and late-onset sNMTC patients. Conclusions: These findings underscore the relevance of age at disease onset in shaping the clinical phenotypes of FNMTC. The distinct pathological features of early-onset vs late-onset FNMTC suggest different pathophysiological mechanisms, with the former likely driven by direct genetic/oncogenic alterations, and the latter influenced by autoimmune thyroiditis–related carcinogenesis, a hypothesis that warrants further investigation in larger prospective studies.